ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2602G>C (p.Ala868Pro) (rs727504356)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000475271 SCV000204154 likely pathogenic Hypertrophic cardiomyopathy 2019-07-23 criteria provided, single submitter clinical testing The p.Ala868Pro variant in MYH7 has been reported in at least 8 individuals with HCM (Millat 2010, Walsh 2017, LMM data, Invitae personal communication, ClinVar Variation ID 177847), including 1 individual with early-onset HCM who also carried a pathogenic variant in the MYBPC3 gene. It has also been reported to segregate with HCM in one affected family member (ClinVar submission SCV000924872.1). This variant was absent from large population studies. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. However, this variant lies in the head region of the protein and missense variants in this region are statistically more likely to be disease-associated (Walsh 2016). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PM1, PM2, PS4_Moderate.
GeneDx RCV000766436 SCV000208486 uncertain significance not provided 2017-10-27 criteria provided, single submitter clinical testing The A868P variant of uncertain significance in the MYH7 gene has been previously reported in two unrelated individuals with a clinical diagnosis of HCM, and did not detect the variant in 400 control chromosomes, however no additional family segregation information was provided. One reported individual who was diagnosed with HCM at one year of age was also heterozygous for a pathogenic variant in the MYBCP3 gene (Millat et al., 2010). The A868P variant was not identified in 400 published control chromosomes (Millat et al., 2010), and was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A868P variant results in a semi-conservative amino acid substitution in the cardiac ß-myosin heavy chain at a position that is conserved throughout evolution. Consequently, in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, additional evidence is needed to determine whether this variant is pathogenic or benign.
Invitae RCV000475271 SCV000546246 pathogenic Hypertrophic cardiomyopathy 2019-10-09 criteria provided, single submitter clinical testing This sequence change replaces alanine with proline at codon 868 of the MYH7 protein (p.Ala868Pro). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported in more than four unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 2062450, 27532257, Invitae). ClinVar contains an entry for this variant (Variation ID: 177847). A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000622129 SCV000737025 likely pathogenic Cardiovascular phenotype 2019-10-01 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Structural Evidence;Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Color RCV001189962 SCV001357362 likely pathogenic Cardiomyopathy 2020-03-25 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000766436 SCV000924872 uncertain significance not provided 2017-04-21 no assertion criteria provided provider interpretation This patient has a diagnosis of HCM and had a Comprehensive Cardiomyopathy Panel with the GeneDx laboratory. The test included sequencing of 76 genes and additional deletion/duplication analysis of 60 of those genes (nuclear genes) associated with various forms of cardiomyopathy: ABCC9, ACTC (ACTC1), ACTN2, ANKRD1, BAG3 , BRAF, CAV3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, DTNA, EMD, FKTN, GATAD1, GLA, HRAS, ILK, JPH2, JUP, KRAS, LAMA4, LAMP2, LDB3 (ZASP), LMNA, MAP2K1, MAP2K2, MTND1, MTND5, MTND6, MTTD, MTTG, MTTH, MTTI, MTTK, MTTL1, MTTL2, MTTM, MTTQ, MTTS1, MTTS2, MYBPC3, MYH7, MYL2, MYL3, MYLK2, MYOZ2, MYPN, NEBL , NEXN, NRAS, PDLIM3, PKP2, PLN, PRKAG2, PTPN11, RAF1, RBM20, RYR2, SCN5A, SGCD, SOS1, TAZ, TCAP, TMEM43, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, VCL. 7 variants were reported. We believe the MYH7 variant is the most likely to be pathogenic: • p.Ala868Pro (A868P; c.2602G>C) in the MYH7 gene • p.Leu327Val (L327V; c.979C>G) in the PRKAG2 gene • p.Pro323Thr (P323T; c.967C>A) in the GLA gene • p.Ala749Ile (A749I; c.2245_2246delGCinsAT) in the PKP2 gene • p.Met89Thr (M89T; c.266T>C) in the JUP gene • p.Asp2771Ala (D2771A; c.8312A>C) in the DMD gene • Duplication of at least exons 1-2 of the LAMA4 gene Given the large number of genes included on this panel, and the large and variable nature of some of these genes, it is expected that most individuals (including individuals who don't have inherited cardiac disease) would have at least one and possibly several rare variants found with this test. As a result, it is important to consider the data available on each variant to determine whether it is a disease-predisposing variant or one of the many benign rare variants that we all have in our DNA. p.Ala868Pro (A868P; c.2602G>C) in exon 22 of the MYH7 gene (NM_000257.2) Chromosome position: 14:23894055 C / G Based on the information reviewed below, including the presence in cases with HCM, the absence in general population controls, and the likely structural disruption this variant would cause to the protein, we classify it as a Variant of Uncertain Significance (VUS)-probably disease causing, concluding that it is highly suspicious but that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing in at-risk relatives at this time. The Laboratory for Molecular Medicine and Invitae have both submitted it to ClinVar as a VUS. This variant has previously been reported in at least 3 individuals with a stated diagnosis of HCM. Alfares et al. from the Laboratory for Molecular Medicine reported it in 2015 in one person tested for HCM at their laboratory. Millat et al. (2010) reported it in 2 unrelated French probands clinically diagnosed with HCM. However, one of these individuals (diagnosed at one year of age) also had a missense variant in the MYBPC3 gene: p.Arg1022Pro (Millat et al. 2010). There is no published segregation data for Ala868Pro. However, in our patient’s family the variant does segregate with disease in this patient and her daughter who have both been clinically diagnosed with HCM. This is a conservative amino acid change, resulting in the replacement of a nonpolar Alanine with a nonpolar Proline. However, this residue falls within the S2 subfragment of myosin (residues 848-1216; Colegrave and Peckham 2014), which is a highly repetitive amino acid sequence at the beginning of the rod domain that forms an alpha-helical coiled-coil structure. Proline is known to break alpha helices, and it could therefore disrupt the structure of this protein domain or disrupt the higher-order formation of sarcomere thick filaments. Alanine at this location is highly conserved across vertebrate species. The surrounding residues are also highly conserved. Nearby residue p.Arg870His is considered solidly Pathogenic by multiple submitters to ClinVar. In silico analysis with PolyPhen-2 predicts the Ala868Pro variant to be “Possibly Damaging” with a score of 0.929. According to MutationTaster predicts it to be “Disease Causing” and SIFT predicts it to be “Damaging”. In total the variant has not been seen in >140,000 published controls and individuals from publicly available population datasets. The variant was not observed in published controls: 200 French Caucasians (Millat et al. 2010). This variant is absent from the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. Our patient’s ancestry is Latino. Ancestry-matched individuals can be found in greater numbers in the ExAC database of 60,000 exomes from disease-specific and population genetic studies (with efforts made to exclude individuals with severe pediatric diseases). ExAC currently contains 5778 “Latino” individuals. This variant is not present in ExAC. There is good coverage at this site: Almost all individuals are covered at 30x, with mean and median coverage close to 80x. These individuals took part in a range of disease-specific and population genetic studies, and the curators made an effort to exclude individuals with severe pediatric diseases. This variant is also not present in the gnomAD database, which is an expansion of ExAC to include variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. There is 1 Latino individual in gnomAD with a different amino acid change at this location: p.Ala868Ser.

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